CN111500703B - 一种鉴定家族性渗出性玻璃体视网膜病变的引物、试剂、试剂盒、方法及其应用 - Google Patents
一种鉴定家族性渗出性玻璃体视网膜病变的引物、试剂、试剂盒、方法及其应用 Download PDFInfo
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Abstract
本发明公开了一种鉴定家族性渗出性玻璃体视网膜病变的引物、试剂、试剂盒、方法及其应用，涉及疾病相关突变基因。鉴定方法包括鉴定待测基因与CTNNA1基因全长序列相比，是否具有如下至少一种的突变：c.215T>C、c.2678C>T和c.1125_1131delCAGGGAC。发明人提出了新的家族性渗出性玻璃体视网膜病变(FEVR)致病基因，并提供了该致病基因的三个突变位点，这对家族性渗出性玻璃体视网膜病变的鉴定、早期分子筛查、家族遗传研究和遗传咨询具有重要的意义。
Description
技术领域
本发明涉及疾病相关突变基因，具体而言，涉及一种鉴定家族性渗出性玻璃体视网膜病变的引物、试剂、试剂盒、方法及其应用。
背景技术
家族性渗出性玻璃体视网膜病变(Familial exudative vitreoretinopathy，以下简称FEVR)是一类遗传性视网膜病变，它是由先天性视网膜血管发育异常引起的多种小儿视网膜病变之一。该病的临床表现为视网膜表层血管发育迟缓、周围血管缺失、渗漏和新生血管等，严重者可发生视网膜牵拉和脱落并最终导致失明，若不进行及时干预，将对患者的生活造成严重影响。
目前，共有12个已报道的FEVR基因，但这些基因突变仅能解释约50％左右的FEVR病例，留下50％的病例无法用遗传学解释。
鉴于此，特提出本发明。
发明内容
本发明的目的在于提供一种鉴定家族性渗出性玻璃体视网膜病变的引物、试剂、试剂盒、方法及其应用以解决上述技术问题。
本发明是这样实现的：
一种用于鉴定家族性渗出性玻璃体视网膜病变的引物，上述引物用于鉴定待测基因与CTNNA1基因全长序列相比是否具有如下至少一种的突变：
c.215T>C、c.2678C>T和c.1125_1131delCAGGGAC；CTNNA1基因为ENSG00000044115基因。
优选地，引物为具有如下至少一组序列的引物：SEQ ID NO.3和SEQ ID NO.4；SEQID NO.5和SEQ ID NO.6；SEQ ID NO.7和SEQ ID NO.1。
CTNNA1基因位于人的5号染色体上，Ensembl:ENSG00000044115，现有的研究显示该基因编码连接蛋白家族的一个成员，CTNNA1蛋白在细胞粘附过程中发挥重要作用的方式包括将位于质膜上的钙粘着蛋白连接到细胞内的肌动蛋白丝。CTNNA1编码的蛋白包含三个黏着斑蛋白同源域，并响应于细胞骨架张力而经历构象变化，从而导致钙粘着蛋白-肌动蛋白丝连接的重构。
CTNNA1基因在NCBI的序列号为NG_047029.1。
发明人创造性的发现CTNNA1基因的三个致病突变位点与家族性渗出性玻璃体视网膜病变相关，并研究了CTNNA1基因的三个致病突变位点对蛋白功能的影响。
利用全外显子测序技术筛查46个FEVR家系的致病相关突变，发明人筛查得到一个新的FEVR致病基因CTNNA1及其三个致病突变。三个致病突变分别为：
CTNNA1基因的第215位的T突变为C，对应的第72位氨基酸由Phe突变为Ser；CTNNA1基因的第2678位的C突变为T，对应的第893位氨基酸由Pro突变为Leu；CTNNA1基因的第1125位至1131位发生碱基CAGGGAC的缺失，对应的第376位氨基酸是首个发生移码突变的氨基酸，由Arg突变为Cys，同时发生移码突变后，终止密码的位置变为第27位。
SEQ ID NO.3和SEQ ID NO.4用于检测CTNNA1基因是否发生c.215T>C；SEQ IDNO.5和SEQ ID NO.6用于检测CTNNA1基因是否发生c.2678T>C；SEQ ID NO.7和SEQ ID NO.1用于检测CTNNA1基因是否发生c.1125_1131delCAGGGAC。
一种使用上述引物进行家族性渗出性玻璃体视网膜病变的鉴定方法，鉴定方法为非疾病的诊断目的，鉴定方法包括使用引物对待测基因进行PCR扩增。
在本发明应用较佳的实施方式中，上述进行PCR扩增的反应程序为：95-98℃5-8min；95-98℃20-30s，60-60.5℃25-30s，70-72℃25-30s，重复30-40次；70-72℃1-5min。
在其他实施方式中，上述PCR扩增反应的程序可以根据实际扩增反应的需求进行自适应调整，可以适当延长或缩短反应时间，循环次数，调节反应的温度。
在本发明应用较佳的实施方式中，上述鉴定方法还包括用PCR扩增的产物进行电泳或测序。
通过对PCR扩增的产物进行电泳，根据扩增条带的大小及有无来判断待测基因是否发生突变。
采用测序方法鉴定家族性渗出性玻璃体视网膜病变的方法包括如下步骤：
(1)提取待测样本的基因组DNA；
(2)分别用上述测序引物进行测序；
(3)比对CTNNA1参照序列(ENSG00000044115)和待测样本的测序结果。
在本发明提供的一种实施方式中，上述序列测定是Sanger序列测定。
在本发明应用较佳的实施方式中，上述鉴定方法还包括鉴定鉴定待测基因编码的氨基酸序列与SEQ ID NO.2相比，是否具有如下至少一种的突变：
p.F72S、p.P893L和p.R376Cfs*27。
一种用于鉴定家族性渗出性玻璃体视网膜病变的试剂，试剂为非疾病的诊断目的，其包括上述引物。
在一些实施方案中，本发明中所述的非诊断疾病的目的包括但不限于研究SNP分布和多肽性，用于家族演化研究。这样的应用是本领域技术人员可以理解的。
通过家系研究发现，CTNNA1基因的三个突变均为常染色体显性遗传。三个突变分别在CTNNA1蛋白的三个不同结构域中，暗示该蛋白在视网膜血管发育中可能发挥了重要作用。
一种用于鉴定家族性渗出性玻璃体视网膜病变的试剂盒，试剂盒为非疾病的诊断目的，其包括上述试剂。
在本发明应用较佳的实施方式中，上述试剂盒还包括PCR缓冲液。
PCR缓冲液中包含PCR反应的Taq酶，dNTP，Mg离子，钙离子，硫酸根离子。
一种使用上述引物、试剂或试剂盒在家族性渗出性玻璃体视网膜病变鉴定中的应用，应用以非疾病的诊断为目的。
在其他实施方式中，上述应用还包括在家族性渗出性玻璃体视网膜病变早期分子筛查中的应用。
一种使用上述引物在制备家族性渗出性玻璃体视网膜病变检测试剂中的应用。
一种使用上述试剂在制备家族性渗出性玻璃体视网膜病变检测试剂盒中的应用。
本发明具有以下有益效果：
本发明提供了一种鉴定家族性渗出性玻璃体视网膜病变的引物、试剂、试剂盒、方法及其应用，发明人提出了新的家族性渗出性玻璃体视网膜病变(FEVR)致病基因，并提供了该致病基因的三个突变位点，这对家族性渗出性玻璃体视网膜病变的鉴定、早期分子筛查、家族遗传研究和遗传咨询具有重要的意义。
附图说明
为了更清楚地说明本发明实施例的技术方案，下面将对实施例中所需要使用的附图作简单地介绍，应当理解，以下附图仅示出了本发明的某些实施例，因此不应被看作是对范围的限定，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他相关的附图。
图1为FEVR患者和正常人的眼底荧光造影造影结果；
图2为CTNNA1突变的家系图和Sanger测序结果；
图3为免疫共沉淀实验考察突变对CTNNA1蛋白相互作用的影响；
图4为细胞免疫荧光法考察点突变CTNNA1对蛋白亚细胞定位和人视网膜血管内皮细胞骨架的影响；
图5为CTNNA1及其突变对Wnt信号通路活性的影响。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚，下面将对本发明实施例中的技术方案进行清楚、完整地描述。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市售购买获得的常规产品。
以下结合实施例对本发明的特征和性能作进一步的详细描述。
实施例1
本实施例提供了一种鉴定家族性渗出性玻璃体视网膜病变的引物及试剂盒。
利用全外显子测序技术筛查46个FEVR家系的致病相关突变，从中筛选出3个FEVR家系，Family-3016，Family-34和Family-3004。发现这3个家系的CTNNA1基因分别存在如下基因突变：c.215T>C；p.F72S(简称F72S)、c.1125_1131delCAGGGAC；p.R376Cfs*27(该突变为移码突变，简称R376Cfs*27)和c.2678C>T；p.P893L(简称P893L)。
这3个家系的临床检测方式主要为眼底荧光造影(Fundus fluoresceinangiography，FFA)，如图1所示，FEVR患者的视网膜周围血管发育缺如，且出现新生血管和渗漏的表型。
本实施例利用Sanger测序验证突变，使用的测序引物参照表1所示。
表1 Sanger测序引物
采用表1中的引物对家系成员DNA样品进行PCR，总的反应体系为10μL，反应体系参照表2所示，并利用本实施例提供的试剂盒进行测序，该试剂盒包括2×PCR Mix(PCR缓冲液)。
表2 Sanger测序PCR反应体系
PCR反应的条件为：首先在95℃预变性5min；然后在95℃变性30s，60℃退火30s，在72℃延伸反应30s，重复34个循环；循环结束后在72℃下保温2min。
PCR完成后上机进行Sanger测序。本实施例中3个FEVR疾病家系图、Sanger测序图和突变位点示意图参照图2所示，图2中黑色箭头为先证者(家系中最先发病的患者)，测序箭头指向突变位点，家系图中圆形为女性，正方形为男性，实心为家系中的具有临床表型的FEVR患者，空心为家系中的正常人。
由图2可以看出，具有临床表型的患者均为杂合突变携带者，表明三个突变均在各自家系中与疾病表型共分离，且符合常染色体显性遗传规律。
图2中也示出了发生突变的CTNNA1基因在多个物种中保持高度保守。由Sanger测序结果可知，Family-3016，Family-34和Family-3004这3个家系的CTNNA1基因分别存在如下基因突变：c.215T>C、c.1125_1131delCAGGGAC和c.2678C>T。
由图2可以看出，三个突变分别在CTNNA1蛋白的三个不同结构域中，暗示该蛋白在视网膜血管发育中可能发挥了重要作用。
实施例2
为了探究实施例1中CTNNA1基因突变对蛋白功能的影响，本实施例利用免疫共沉淀技术考察点突变对CTNNA1蛋白相互作用能力的影响。
在汉恒生物购买了三种CTNNA1的点突变腺病毒(adenovirus)，将其感染到人视网膜血管内皮细胞中，并利用免疫共沉淀技术考察点突变对CTNNA1蛋白相互作用能力的影响。
免疫共沉淀实验结果参照图3所示，由图3可以看出，R376Cfs*27移码突变可能造成无义介导的mRNA降解，最终导致蛋白缺失；而F72S突变显著影响了CTNNA1与CTNNB1的相互作用以及CTNNA1与VE-CADHERIN的相互作用。
CTNNB1基因编码的CTNNB1蛋白质是构成粘附连接(AJs)的蛋白质复合物的一部分，该蛋白调节细胞的生长和细胞之间的粘附，AJ对于创建和维持上皮细胞层是必需的。编码的蛋白质还锚定肌动蛋白的细胞骨架。
VE-CADHERIN为血管内皮细胞钙粘连蛋白，是血管内皮细胞(EC)之间粘着连接(adherens junctions)的关键分子，其结构和功能异常会导致EC粘着连接解离。
用CTNNB1蛋白和VE-CADHERIN蛋白作为互作参比蛋白，从而鉴定CTNNA1基因突变后的CTNNA1蛋白功能。
实施例3
本实施例利用细胞免疫荧光实验考察点突变对CTNNA1蛋白的亚细胞定位和人视网膜血管内皮细胞骨架的影响。由于R376Cfs*27移码突变导致蛋白缺失，因此不在此做探讨，本实施例仅对P893L突变和F72S突变进行研究。
细胞免疫荧光法亚细胞定位结果参照图4所示，由图4可以看出，野生型和P893L突变CTNNA1蛋白正常表达在细胞膜位置，而F72S突变导致了蛋白无法定位到细胞膜上，仅存在于细胞质内，暗示F72S突变可能显著影响了该蛋白功能。
此外，相比于空载对照(Vector)病毒，过表达野生型CTNNA1(Ad WT)并不影响人视网膜血管内皮细胞的细胞骨架排布，而P893L突变和F72S突变导致了细胞骨架排布紊乱，暗示这两个突变可能影响到了蛋白功能。
实施例4
本实施例利用HEK 293STF细胞系和双荧光素酶报告基因实验考察了CTNNA1突变对该蛋白Wnt信号通路调控能力的影响。
由于Wnt信号通路异常是导致FEVR的重要因素，我们考察了CTNNA1突变对CTNNA1蛋白Wnt信号通路调控能力的影响。
利用HEK 293STF细胞系和双荧光素酶报告基因实验，HEK 293STF细胞系(约翰霍普金斯大学赠送)中已稳定转染有TOP-FLASH质粒(该质粒含有7×TCF/LEF转录结合位点，其下游为萤火虫荧光素酶的编码基因)，一旦Wnt信号通路被激活，即可促进TCF/LEF结合到转录结合位点上，从而激活萤火虫荧光素酶的表达。
我们在细胞中共转染Wnt信号通路重要蛋白(FZD4、NDP、LRP5和PGL4.1)和空载质粒(Vector)、野生型质粒(WT)、F72S突变质粒、P893L突变质粒或P893L突变质粒，其中FZD4、NDP和LRP5为Wnt信号通路激活所需的蛋白，PGL4.1所编码的海参荧光素酶为内参蛋白，利用双荧光素酶报告基因试剂盒(Promega，E1910)，加入反应底物后在多功能酶标仪中分别测定萤火虫荧光和海参荧光，萤火虫荧光和海参荧光的荧光比值则为相对Norrin/β-catenin信号通路活性，以考察CTNNA1及其突变对Norrin/β-catenin信号通路活性的影响。
由图5可以看出，野生型CTNNA1相比Vector空载而言显著抑制Wnt信号通路(抑制了约62％的活性)，暗示CTNNA1在体内可能通过抑制Wnt信号通路而调控血管发育。Vector空载的Wnt信号通路活性比野生型CTNNA1的Wnt信号通路活性更高，这是由于野生型CTNNA1对Wnt信号通路活性存在抑制作用，而空载因未表达任何蛋白而不存在抑制作用。
相比野生型CTNNA1，F72S、R376Cfs*27和P893L突变均显著上调了Wnt信号通路活性，分别约为2.5倍、2.7倍和1.4倍，暗示CTNNA1突变可能通过激活Wnt信号通路从而导致FEVR。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
SEQUENCE LISTING
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Claims (2)
1.一种鉴定家族性渗出性玻璃体视网膜病变的引物在制备家族性渗出性玻璃体视网膜病变检测试剂中的应用，其特征在于，所述引物用于鉴定待测基因与CTNNA1基因全长序列相比是否具有如下至少一种的突变：
c.215T>C、c.2678C>T和c.1125_1131delCAGGGAC；所述CTNNA1基因为ENSG00000044115基因；
所述引物为具有如下至少一组序列的引物：SEQ ID NO.3和SEQ ID NO.4；SEQ ID NO.5和SEQ ID NO.6；SEQ ID NO.7和SEQ ID NO.1。
2.一种鉴定家族性渗出性玻璃体视网膜病变的试剂在制备家族性渗出性玻璃体视网膜病变检测试剂盒中的应用，其特征在于，所述试剂包括引物，所述引物用于鉴定待测基因与CTNNA1基因全长序列相比是否具有如下至少一种的突变：
c.215T>C、c.2678C>T和c.1125_1131delCAGGGAC；所述CTNNA1基因为ENSG00000044115基因；
所述引物为具有如下至少一组序列的引物：SEQ ID NO.3和SEQ ID NO.4；SEQ ID NO.5和SEQ ID NO.6；SEQ ID NO.7和SEQ ID NO.1。
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